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ECULIZUMAB TREATMENT OF PAEDIATRIC PATIENTS WITH ATYPICAL HAEMOLYTIC URAEMIC SYNDROME: FIRST PROSPECTIVE CLINICAL TRIAL

Rees L,1 Greenbaum LA,2 Fila M,3 Tsimaratos M,4 Ardissino G,5 Al-Akash SI,6 Evans J,7 Henning P,8 Lieberman KV,9 Maringhini S,10 Pape L,11 van de Kar N,12 Vande Walle J,13 Ogawa M,14 Bedrosian CL,14 Licht C15

1Great Ormond Street Hospital for Children, London, UK; 2Emory University, Atlanta, USA; 3Hôpital Robert-Debré, Paris, France; 4Hôpital de la Timone, Marseille, France; 5Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; 6Driscoll Children’s Hospital, Corpus Christi, USA; 7Nottingham University Hospitals, Nottingham, UK; 8Women’s and Children’s Hospital, North Adelaide, Australia; 9Hackensack University Medical Center, Hackensack, USA; 10G. Di Cristina Children’s Hospital, Palermo, Italy; 11Hannover Medical School, Hannover, Germany; 12Radboud University Medical Centre, Nijmegen, The Netherlands; 13University Hospital Ghent, Ghent, Belgium; 14Alexion Pharmaceuticals, Cheshire, USA; 15The Hospital for Sick Children, Toronto, Canada

INTRODUCTION: Atypical haemolytic uraemic syndrome (aHUS) is a rare, genetic, life-threatening disease in which uncontrolled complement activation leads to systemic thrombotic microangiopathy (TMA) and severe end-organ damage. Eculizumab (Ecu) is a terminal complement inhibitor approved for the treatment of aHUS. Retrospective data and case reports have previously shown Ecu to be safe and effective for paediatric patients (pts) with aHUS. We now report results from the first prospective clinical trial in children.

METHODS: Children with aHUS were recruited into an open-label, 26-week, single-arm, phase 2 study, with Ecu dosing determined by weight as per approved dosing. Inclusion criteria included platelet count <lower limit of normal at screening , lactate dehydrogenase (LDH) ≥1.5´ upper limit of normal (ULN) at the start of TMA and serum creatinine ≥97th percentile for age at screening. Pts with STEC-HUS (Shiga toxin and E. coli) and severe ADAMTS13 deficiency (activity <5%) were excluded. Assessments included complete TMA response (primary endpoint: platelet and LDH normalisation [>150 ´ 109/L and < ULN, respectively], and ≥25% decrease in serum creatinine from baseline), platelet normalisation, estimated glomerular filtration rate (eGFR) increase and plasma exchange/plasma infusion (PE/PI)-free status.

RESULTS: 22 pts were enrolled (mean age 6.5 years [range, 1 month to 17 years]; 10 [45%] females; 10 [45%] with an identified complement mutation or antibody). 16 (73%) pts were newly diagnosed with aHUS (a median of 6 days prior to Ecu treatment). 19 (86%) pts completed 26 weeks of Ecu treatment. Outcomes improved as shown in Table 1. Dialysis was discontinued by 9/11 (82%) pts receiving this at baseline, with the other 11 pts remaining dialysis free. All 10 pts managed with PE/PI at baseline discontinued PE/PI. Ecu was well tolerated and no safety concerns became apparent. There were no meningococcal infections and no deaths.

Table 1. Outcomes in paediatric pts with aHUS at median 26 weeks of Ecu treatment

Complete TMA response, n (%) / 14 (64%) 95% CI 41-83
Platelet normalisation, n (%) / 21 (95%) 95% CI 77-100
eGFR increase of ≥15 mL/min/1.73m2 from baseline, n (%) / 19 (86%) 95% CI 65-97
Mean (95% CI) eGFR increase from baseline, mL/min/1.73m2 / 64 (50, 79); P<0.0001, week 27

CONCLUSION: This first prospective trial of Ecu treatment in paediatric pts with aHUS confirmed inhibition of complement-mediated TMA. Early intervention with Ecu improved haematologic and renal parameters, and decreased the burden of dialysis. In paediatric pts with aHUS, treatment with Ecu as first-line therapy is effective and well tolerated at the approved dose regimen. The clinical trial is continuing.